Alopecia (baldness), a deficiency of hair, either normal or abnormal, is primarily a cosmetic problem in humans. It is a deficiency of terminal hair, the broad diameter, colored hair that is readily visible to the eye. However, in the so-called bald person, although there is a noticeable absence of terminal hair, the skin does contain vellus hair (a fine colorless hair) which may require microscopic examination to be seen. This vellus hair may be a precursor to terminal hair.
It is known that the 1,2-dihydro-1-hydroxypyrimidines of formula (I), when used systemically, are useful as antihypertensive agents. ##STR1## In these compounds, R.sub.3 and R.sub.2 may be hydrogen, lower alkyl, lower alkenyl, lower aralkyl, or lower cycloalkyl and, taken together, R.sub.3 and R.sub.2 may be a heterocyclic group, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino and 4-lower-alkylpiperazinyl, where each of these heterocyclic groups may have up to three lower alkyl, hydroxy, or alkoxy substituents. R.sub.1 may be hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lower cycloalkyl, lower aryl, lower aralkyl, lower alkaryl, lower alkaralkyl, lower alkoxyaralkyl or lower haloaralkyl. It has also been taught that when these compounds are administered topically they act to stimulate the conversion of vellus hair to terminal hair and prevent the transformation of terminal hair to vellus hair. In short, the topical use of these compounds has been taught to increase the growth of perceivable mammalian hair.
The art is replete with disclosures of topical vehicles which are said to improve the penetration of a variety of pharmaceutical actives through the skin. Indeed, it is well-recognized that the development of such vehicles would provide a very useful method for the delivery of pharmaceuticals. It has been taught that a binary penetration system comprising specific polar lipid cell-envelope disordering compounds, such as oleic acid or methyl laurate, together with specific diol compounds, such as propylene glycol, can be used to topically deliver systemic levels of selected pharmaceutical agents, such as steroids and non-steroidal antiinflammatory agents. However, these vehicles have not been found to be equally effective for enhancing the delivery of all pharmaceutical agents.
In order to be useful as a topical vehicle for a hair-growth stimulating agent, the vehicle must satisfy four stringent requirements:
(1) the vehicle must provide enhanced penetration of the agent through the skin;
(2) the vehicle must have cosmetically-acceptable aesthetics;
(3) the vehicle must not be irritating to the skin; and
(4) the vehicle must be preferentially substantive to the scalp or skin rather than to, for example, the comb or clothing. While some vehicles may satisfy several of these criteria, the best vehicles will be optimum for all of them.
It has now been found that hydroxy iminopyrimidine compounds of the formula (I) can be effectively delivered percutaneously by incorporating them into a specific vehicle which provides an exceptional increase in penetration over conventional vehicles. In addition, this vehicle satisfies all four of the requirements set forth above. Thus, the present invention provides an aesthetically acceptable topical vehicle which can enhance the mammalian hair growth effects of the 1,2-dihydro-1-hydroxy-iminopyrimidine compounds, such as Minoxidil. Specifically, it has been discovered that a specific binary surfactant system comprising a polar lipid compound and a diol or triol compound can consistently and dramatically improve the topical delivery of 1,2-dihydro-1-hydroxyiminopyrimidine compounds (formula (I)).
U.S. Pat. No. 3,461,461, Anthony et al, issued Aug. 12, 1969, discloses a class of 6-amino-1,2-dihydro-1-hydroxy-2-iminopyrimidines and describes the use of these compounds as antihypertensive agents. The topical administration of these compounds to stimulate mammalian hair growth is disclosed in U.S. Pat. No. 4,139,619, Chidsey, III, issued Feb. 13, 1979. Standard aqueous solutions, ointments and creams, such as those based on propylene glycol, ethanol, n-methyl-pyrrolidone, or petrolatum are used for the topical formulations. A closely related group of compounds, 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines, is disclosed in U.S. Pat. No. 3,382,247, Anthony et al, issued May 7, 1968. A process for preparing 6-substituted-4-amino-1,2-dihydro-1-hydroxy-2-iminopyrimidines is taught in U.S. Pat. No. 3,644,364, Anthony, issued Feb. 22, 1972.
U.S. Pat. No. 4,070,462, Ecker, issued Feb. 24, 1978, discloses a topical vehicle which includes (i) 5-15% 1,2-propanediol, 2,3-butanediol or 2-methyl-2,4, propanediol; (ii) 1-3% propylene glycol monostearate; and (iii) petrolatums and waxes to 100%.
European Patent Application 13,459, published July 23, 1980, describes compositions useful in the treatment of acne. These compositions contain benzoyl peroxide, C.sub.6 -C.sub.14 primary alcohols, and a diol selected from 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, and 2,3-butanediol.
European Patent Application 43,738, published Jan. 13, 1982, describes compositions for topical application. The compositions described are suitable for effective delivery of lipophilic, pharmacologically-active compounds using primary alcohols or various carboxylate compounds in combination with selected diols.
European Patent Application 95,813, published Dec. 7, 1983, discloses a binary penetration system utilizing a diol and a cell-envelope disordering compound to aid in the penetration of 9-hydroxyethoxymethyl (and related) derivatives of 6- and 2,6-substituted purines. These purine compounds are reported to be effective in the treatment of viral infections, especially herpes, and can be administered parenterally, orally or topically. 9-(2-hydroxyethoxymethyl) guanine is disclosed as being a particularly preferred active.
U.S. Pat. No. 4,552,872, Cooper, et al, issued Nov. 12, 1985, describes topical pharmaceutical compositions containing corticosteroids and a skin penetration enhancing vehicle comprising selected diols and cell-envelope disordering compounds. These compositions are taught to provide systemically active levels of the corticosteroids via topical administration. A similar disclosure is provided in European Patent Application 129,283, published Dec. 27, 1984.
U.S. Pat. No. 4,557,934, Cooper, issued Dec. 10, 1985, describes pharmaceutical compositions for topical application containing any of a wide range of pharmaceutical actives together with a diol compound and 1-dodecyl-azacycloheptan-2-one. See also European Patent 129,284, published Dec. 27, 1984. U.S. Pat. No. 4,537,776, Cooper, issued Aug. 27, 1985, describes pharmaceutical compositions for topical application containing any of a wide range of pharmaceutical actives together with N-(2-hydroxyethyl)pyrrolidone. A similar disclosure is provided in European Patent Application 129,285, published Dec. 27, 1984.
European Patent Application 171,742, published Feb. 18, 1986, discloses topical compositions which provide systemically active doses of opioids to the user. The penetration enhancing topical vehicle comprises at least one of a saturated fatty acid or fatty alcohol of 8-15 carbon atoms or of an unsaturated fatty alcohol or fatty acid of 8-18 carbon atoms, and a pharmaceutical carrier such as propylene glycol.
1,2-propanediol ("propylene glycol") and the C.sub.10 -C.sub.14 alcohols have been used, separately, in cosmetic and pharmaceutical formulations. In particular, propylene glycol has been described in several articles in the literature as enhancing the penetration of certain pharmacologically active agents, such as the corticosteroids. See Rosuold, J., et al., "Effect of Formulation on In Vitro Release and In Vivo Absorption of Corticosteroids from Ointments", Medd. Novsk Favm Selsk, 44, 21-45 (1982); see also, Anjo, D.M., et al., "Methods for Predicting Percutaneous Penetration in Man", Percutaneous Absorption of Steroids, pp 31-51, Academic Press, New York, N.Y. (1980).
U.S. Pat. No. 3,535,422, Cox, et al., Oct. 20, 1970, relates to stable benzoyl peroxide compositions containing organic emollients selected from C.sub.4 -C.sub.20 aliphatic alcohols, C.sub.2 -C.sub.3 glycols, C.sub.12 -C.sub.20 fatty acids and their esters, and mixtures thereof.
U.S. Pat. No. 4,070,462, Ecker, issued Jan. 24, 1978, describes topical steroid compositions containing 6% propylene glycol and 1% propylene glycol monostearate.
Canadian Patent 1,072,009, Sipos, issued Feb. 19, 1980, describes topical antimicrobial compositions containing C.sub.5 -C.sub.10 straight chain alcohols or C.sub.17 branched chain alcohols in which the longest chain is C.sub.5 -C.sub.10.
CA 92: 153, 181j describes an indomethacin ointment containing 10% propylene glycol and 1.1% disopropanolamine.
B. Idson, Cosmetics & Toiletries, 95, 59 (1980), states that the factors affecting drug penetration and, consequently in most cases, effectiveness, are complex. He observes that the vehicle that provides ideal penetration conditions for one drug may prove unsatisfactory for another. The author concludes that prediction is not simple and product suitability must be assessed by human trials.
U.S. Pat. No. 4,299,826, Luedders, issued Nov. 10, 1981, describes a composition for the treatment of acne which includes diisopropyl sebacate in combination with an alcohol as a penetration enhancer for an erythromycin derivative.